1. Technical Field of the Invention
The present invention relates to novel pharmaceutical preparations of acetylsalicylic acid comprising alcoholic solutions thereof and to percutaneous antithrombotic applications of such novel compositions.
2. Description of the Prior Art
Acetylsalicylic acid (ofttimes "ASA" below) has hitherto principally been administered orally. In the medical arts, ASA is primarily indicated as a nonsteroidal anti-inflammatory drug (NSAID), eliciting anti-inflammatory, analgesic and antipyretic effects. In addition to these, ASA elicits other effects, such as inhibition of thrombocyte aggregation, and is therefore employed in long-term therapy, particularly for reinfarction prophylaxis of cerebral and cardiac infarctions. For this purpose, it has also been administered via the peroral route.
ASA (but not salicylic acid ("SA" below)) causes irreversible acetylation, and consequently prolonged inactivation, of cyclooxygenase. For the blood platelets, which lack a nucleus and which, in contrast to other tissues, cannot replace the cyclooxygenase by fresh synthesis, this irreversible inhibition at the same time indicates inhibition of the synthesis of the proaggregating agent thromboxane for the entire life of the thrombocytes (1 month).
For this reason, it is only ASA, and not its hydrolysis product SA, which exhibits antithrombotic activity.
The requisite dose for preventing thromboembolic complications still has not been finally determined: at present, daily doses of 30-500 mg are recommended, depending on the indication, with the low-dose therapy exhibiting fewer side effects (V. Fuster et al., Circulation, 87, 659-675 (1993)).
ASA is rapidly metabolized to its principal metabolite SA in the gastrointestinal fluids, during absorption in the stomach and intestine and in the blood plasma. Due to the presystemic metabolism, the absolute bio-availability of ASA following peroral administration is only approximately 50%-70% (H. Blume and E. Mutschler, "Bioaquivalenz--Qualitatsbewertung wirkstoffgleicher Fertigarzneimittel Bioequivalence--quality assessment of finished drugs containing the same active compound!," Govi Verlag, 2nd Supplementary Fascicle 1991, acetylsalicylic acid).
The transdermal administration of ASA, which has long been proposed, is particularly advantageous for antithrombotic therapy since, under these circumstances, the ASA is administered systemically, thereby circumventing the gastrointestinal tract.
To date, oral administration has been practised almost exclusively when using ASA for antithrombotic therapies.
Active compound-containing ointments, creams or gels are employed when administering ASA for the local therapy of diseases of the skin or for the treatment of pain, inflammation and/or rheumatic diseases.
The following alternatives have been disclosed for this purpose:
FR-A-7,502,651 describes solutions of ASA in ethanol for the transcutaneous treatment of pain. These ethanolic solutions are, however, incorporated into creams or ointments. Absorption data are not provided.
U.S. Pat. No. 4,219,548 describes alcoholic solutions of ASA which comprise glycerol monooleate and a glycol. ASA is present in concentrations of from 0.5% to 10%. The solutions are suitable for the topical treatment of inflamed tissue. The symptoms which are described as being treatable are essentially skin inflammations (acne).
U.S. Pat. No. 4,460,368 describes a transdermal system ("TDS" below) for administering ASA, in which the ASA is contained in aqueous solution together with solubilizers. No data are provided with regard to the stability of ASA in the formulation or with regard to plasma levels. Pain and inflammation are the indications for the ASA TDS.
EP-A-0,581,587 describes an excipient for the transdermal administration of various pharmaceutically active compounds, including aspirin (=acetylsalicylic acid) as an anti-inflammatory active compound. The excipient obligatorily consists of the three components, fatty acid ester, alcohol and water.
DE-A-3,413,052 and U.S. Pat. No. 4,665,063 describe topical formulations for the treatment of inflammatory dermatological diseases, including alcoholic solutions of ASA in concentrations of &gt;7%. Several solutions were tested on patients suffering from skin diseases, but no data are provided on the absorption of ASA.
The following alternatives have been disclosed or the transdermal administration of acetylsalicylic acid for thrombosis therapy:
WO 92/20343 describes alcoholic ASA solutions for transdermal thrombosis therapy, which solutions comprise propylene glycol as the essential constituent. A slow and slight transcutaneous absorption of the active compound following topical applications is intended.
DE-A-4,241,128 and WO 94/13302 describe ASA plasters for thrombosis treatment. The employment of TDS for long-term use is described without there existing any data on the absorption of the active compound or on the tolerability of such ASA plasters on the skin.